Carrying the APOE ?4 gene allele is the strongest genetic risk factor for developing Alzheimer's disease (AD). In contrast, APOE ?2 gene allele protects against AD. Consequently, identifying the mechanisms by which APOE alleles alter AD risk is very important to public health. The overall goal of this research is to identify the critical mechanisms that distinguish APOE ?2 from APOE ?4 in order to develop interventions that prevent or ameliorate AD risk by mimicking favorable differential effects of the APOE ?2 variant. The objective of this particular project is to test whether brain apoE lipidation differentiates APOE ?2 from APOE ?4 variant. We are interested in how ApoE HDL in the brain regulates the metabolism of the omega-3 (?-3) polyunsaturated fatty acid docosahexaenoic acid (DHA). We recently demonstrated that in patients with mild AD, APOE ?2 carriers have greater cerebrospinal to plasma DHA ratio compared with APOE ?4 carriers. After 18 months of DHA supplementation, APOE ?4 carriers had less delivery of DHA to the brain compared with non-carriers. Using [11C]-DHA PET, we demonstrated that younger APOE4 carriers have a deficit in brain DHA compared with non-carriers. We hypothesize that reduced ApoE4 lipidation underlies the changes in DHA brain delivery in the context of APOE ?4 genotype. To test our hypothesis, we propose in Aim 1 mechanistic studies to identify DHA transport by ApoE HDL both in vivo and in vitro. Using the apoE mimetic peptide CS-6253, we will test whether enhancing the lipidation of apoE4 proteins would enhance the delivery of DHA to the brain in APOE4 mice. In Aim 2, we develop a novel PET imaging technique for assessing [18F]-DHA brain uptake. We assembled an outstanding group of scientists with expertise in neurochemistry, brain imaging and lipid metabolism to complete our study goals. Our project will identify apoE lipidation as a potential therapeutic target for interventions that prevent or ameliorate AD risk by mimicking favorable lipid carrying effects of the APOE ?2 variant.